The long-term objectives are to understand how the morphogenesis and the physiological functions of coronary blood vessels are controlled at the molecular level, and to contribute to the translation of our findings into novel and effective therapeutics for a number of heart diseases. Normal morphogenesis and physiological functions of coronary vessels are critically required for the physiological functions of the heart. Therefore, it may be possible to treat diseased heart conditions by restoring normal morphogenesis and physiological functions of coronary vessels. The specific aims of this proposal are: 1) to test the hypothesis that angiopoietin-1 alone, or angiopoietin-1 with VEGF can effectively enhance coronary angiogenesis, and as a result, can bring a functional benefit to the cardiac adaptation in response to the surgically induced coronary vessel occlusion, 2) to test the hypothesis that the deficiency of an anti- angiogenic factor, angiopoietin-2, leads to enhanced coronary angiogenesis during the cardiac adaptation in response to the surgically induced coronary vessel occlusion, 3) to test the hypothesis that the Akt intracellular signaling pathway is essential and/or sufficient for the angiopoietin-1-induced endothelial sprouting and vessel tubulogenesis in the three- dimensional fibrin gel culture system, an in vitro assay system related to the vessel morphogenesis in vivo, and 4) to test the hypothesis that coronary endothelial cells express a unique set of genes that are essential for the mature physiological functions of coronary vessels. We will accomplish these goals by extensive use of transgenic mice, knock-out mice, sophisticated small animal surgical method, quantitative and qualitative morphometric analyses, a state-of-the-art, non-invasive imaging method, an unique cell culture system, biochemical methods, and molecular biological methods. Upon the completion of these projects we will be able to provide comprehensive in vivo evaluations of the degree of usefulness of angiopoietins and their downstream signaling pathway components in therapeutic angiogenesis. This will have an immediate impact on the improvement of the current strategies for therapeutic angiogenesis in the heart. Furthermore, our studies may provide useful molecular insights into the novel aspects of the physiological functions of coronary vessels. This information may potentially have a future impact on how to enhance the maturation of the physiological functionality of these vessels, a goal where therapies based on angiogenesis alone may fall short.